A primary knowledge of normal mechanisms of immune tolerance and the kind of determinants recognized by autoreactive T cells are required before the immunological events leading to autoimmunity may be understood. Much has been learned about immune tolerance to membrane and secreted antigens, largely through the use of transgenic technology, but there is a gap in knowledge regarding normal mechanisms of tolerance to protein antigens of the nucleus. Yet, the majority of autoantigens, like La/SS-B, targeted in the systemic autoimmune diseases Sjogren?s syndrome and systemic lupus erythematosus are composed of protein and localize to the nucleus. In order for tolerance and autoimmunity to nuclear antigens to be comprehended, it is therefore imperative that nuclear antigens be studied as a special class of antigen. This study will determine mechanisms of T cell tolerance in systemic anti-nuclear autoimmunity using the autoantigen La as a paradigm for protein autoantigens of the nucleus. Using the K02 Independent Investigator Award mechanism, the candidate seeks to obtain protected research time to expand existing funded work on understanding tolerance and autoimmunity to a clinically important nuclear antigen by determining mechanisms of central tolerance to the human La (hLa) neo-self antigen in hLa transgenic (Tg+) mice. Furthermore, the applicant?s interest in the hypothesis that apoptotic debris may be immunogenic or tolerogenic for nuclear antigens will be merged with the funded ROl work (largely presented in the present application) to determine whether apoptosis in the thymus influences central tolerance to the hLa neo-self antigen. These new initiatives will take advantage of the expertise of colleague and collaborator Linda Thompson, a respected T cell developmental biologist, who will play a significant role in facilitating the candidate's career development through personal and professional interactions. The candidate will be freed from institutional administrative duties, excessive grant writing responsibilities, and excessive teaching duties in order for the career development plan to take place. In the remaining work, mechanisms of peripheral tolerance to the La nuclear antigen will be determined by tracking the fate of hLa specific donor T cells in the periphery of recipient mice that either bear or lack the hLa transgene. Co-transfer of hLa Tg+ (tolerant) and hLa Tg- (non-tolerant) T cells will be conducted to determine whether suppression is a mode of tolerance to the La nuclear antigen. Finally, the relative roles of T cells recognizing immunodominant and subdominant determinants in initiating tolerance or autoimmunity to the La nuclear antigen will be resolved by determining whether they can prime T cells capable of providing help for the production of anti-La autoantibodies.